New Cancer Drugs Are Showing Great Promise

Erika Check Hayden

The results of Denise Nichols's genetic test were both a blessing and a curse. After doctors diagnosed her with advanced ovarian cancer in 2009, Nichols, 54, a nurse from Hamden, Conn., was treated with surgery and chemotherapy and tested for genetic glitches that predispose women to breast and ovarian cancer. Her test confirmed a harmful hiccup in the BRCA2 gene that made her 10 to 27 times more likely to develop ovarian cancer than the average woman. But the finding had a bright side: It meant that Nichols could take a promising new drug, one thought to work only in women with defective BRCA genes.

The drug blocks the action of a protein known as PARP that helps tumors in women like Nichols survive by repairing breaks in the DNA of their cells. Last summer, doctors detected rising levels of a cancer-related protein in Nichols's blood--a warning that her cancer might be coming back. Since March, Nichols has been taking the new drug, and her blood protein levels have dropped to near normal. "I want to be the one that this drug works on," she says. "And I don't ever want to have to go back on chemotherapy again."

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Nichols's battle is part of a revolution in cancer treatment that has swept the field in the past two years. Rather than treat all breast or kidney or lung tumors in the same way, doctors are now peering deep into the genetic code of a patient's cancer, personalizing a treatment path according to its specific mutations, and, if not yet providing a cure, often extending lives by many months--and offering hope. Based on a wave of new research, such as a study released in April revealing that the tumors of nearly 2,000 breast cancer patients could essentially be classified into 10 different types of the disease, a growing number of cancer centers now routinely survey patients' cancers for mutations. "There's a small list of genes which we should be fully aware of when we treat patients with target therapeutics," says Frank McCormick, director of the University of California-San Francisco Helen Diller Family Comprehensive Cancer Center. "At some point, the technology of deep sequencing of patients' genomes will become the standard of care."

A rapid pace. The personalized medicine movement is gaining steam because dozens of these "targeted therapies" are now available. Since Herceptin was approved 14 years ago to treat breast cancer in patients whose tumors overproduce a protein called HER2, a mere trickle of tailored therapies followed over the next decade. Then, the pace picked up. Last year, the Food and Drug Administration approved two breakthrough drugs: crizotinib for lung cancer and vemurafenib for melanoma. In lung cancer patients whose tumors express a version of the anaplastic lymphoma kinase (ALK) gene that is incorrectly fused to a separate gene, crizotinib blocks a tumor-promoting protein made by the fused gene. Vemurafenib inhibits a protein made by a gene called BRAF in the roughly half of melanoma patients who have an overactive form of BRAF. In preliminary results from a trial that was promising enough that it was stopped early, nearly 50 percent of the patients taking vemurafenib saw their tumors recede, compared to fewer than 6 percent of the patients being treated with standard chemotherapy. Last year will be remembered as the year that personalized medicine really began to take off as a weapon against cancer, says Stafford O'Kelly, president of Des Plaines, Ill.-based Abbott Molecular, which developed a test for the ALK mutation.

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Most of the new drugs block the action of genes called oncogenes that, when mutated, send unchecked growth signals to cancer cells. A number of cancers share a faulty version of an oncogene called epidermal growth factor receptor (EGFR), for example; medications now exist to foil its action in patients with colorectal cancer, head and neck cancers, lung cancer, and pancreatic cancer. Imatinib, known by the brand name Gleevec, has proved to be a true lifesaver in the treatment of chronic myelogenous leukemia caused by a glitch that turns on an oncogene that's part of a class called receptor tyrosine kinases. It is now also approved to treat more than seven other cancers caused by receptor tyrosine kinases, including gastrointestinal tumors and some skin tumors.

Other targeted treatments act like the PARP inhibitor used to treat Denise Nichols: They cause cells to commit suicide. A drug used against multiple myeloma and other blood cancers, for example, causes malignant cells to die by preventing them from clearing out broken and malfunctioning proteins. Still others prevent the growth of new blood vessels that feed tumors. And some drugs combine two functions. One guides the molecule to pro-cancerous proteins, and a second contains some toxic element to kill the cancer cell.

Because drugs are still approved by regulators to treat specific diseases, not mutations alone, it's becoming important for doctors and patients to know what mutations in a tumor might make it responsive to a drug, even if the drug is not approved for that type of tumor. Fortunately, the technology for surveying hundreds of different genetic traits at once has become relatively cheap and easy to use within the past five years. So some leading cancer centers, including Massachusetts General Hospital, Memorial Sloan-Kettering in New York, MD Anderson in Houston, and Vanderbilt in Nashville, are now regularly using genotyping to hunt for glitches in many genes at once.

After Hammond, La., attorney Thomas Waterman, 63, was diagnosed with colon cancer in 2005, he underwent surgery, and later further surgery and chemotherapy when his cancer spread. This year, he enrolled in a clinical trial at MD Anderson in which sequencing of 50 genes from his tumor revealed a mutation in EGFR that might render his cancer vulnerable to a drug approved not for his disease but for lung and pancreatic cancer; he began taking the drug in May. Waterman's doctor at MD Anderson, Scott Kopetz, estimates that perhaps half of the patients enrolled in the trial so far are able to find nonstandard treatments to try. "What has changed this year is the realization that this is going to be the norm rather than the exception, and cancer centers will need to start programs that do this routinely," says José Baselga, chief of the division of hematology/oncology at Massachusetts General Hospital Cancer Center, where physicians screen patients' tumors for more than 150 cancer-causing mutations in some 20 genes. (They test in patients whose cancer has spread; people with contained tumors are often better served by surgery.)

A cancer patient whose hospital doesn't offer the screening can turn to private companies for genetic analysis. Foundation Medicine, based in Cambridge, Mass., reads out the entire genetic sequence of nearly 200 genes from a patient's tumor to discover telltale signs that her cancer might respond to approved or experimental targeted treatments. The company says that it has found an average of about three clinically relevant genetic glitches in each of the 400 patients whose tumors it had analyzed as of early summer. The test costs $5,800, though Foundation Medicine president and chief executive Michael Pellini says it is sometimes covered by insurance.

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Immune system boosters. For some cancers, there are no treatments yet that target particular genetic mutations, and many patients don't have a mutation known to respond to a drug. That was the position that Valerie Esposito, now 41, found herself in four years ago. Esposito, a Long Island, N.Y., mother of three, was first diagnosed with melanoma in 2004 and had surgery to remove a tumor from her back. In 2008, doctors noticed that her cancer had spread to her lungs and spleen. Surgery and chemotherapy proved fruitless.

So Esposito's doctors at Memorial Sloan-Kettering offered her an experimental drug, ipilimumab, one of a class of new treatments that boost a patient's own immune defenses against cancer rather than attacking the cancer itself. Esposito began taking ipilimumab in the fall of 2009. Her tumors stayed about the same size for a year and a half; then, a few months after radiation therapy to treat a painful tumor pressing on her spine, all of her tumors but one shrank away. "I had just come home from getting a CAT scan, and I didn't even make it in the front door of my house before my doctor was calling and telling me the good news," recalls Esposito, whose spinal tumor has also stopped growing. Last year, regulators approved ipilimumab after clinical trials found that it was the first treatment ever to prolong the lives of patients with advanced melanoma.

Doctors and scientists have discussed the idea of immunotherapy for more than a century. The concept seems simple: The body's immune system provides natural defenses against cancer, so why not strengthen these defenses by causing natural brakes on the immune system to fail, or by triggering immune response accelerators? But only in the past two years has understanding of the immune system advanced far enough to produce ipilimumab and the controversial prostate cancer vaccine, Provenge, approved in 2010.

Ipilimumab blocks a molecule called CTLA-4 from doing its usual job: dampening down the activity of the immune system's "killer" T cells that normally attack diseased cells and foreign invaders. Provenge is made by infusing a patient's own immune cells with a combination of two proteins that stimulate the cells to attack prostate cancer cells. Neither of these drugs is a miracle cure: Questions have been raised about whether Provenge really does any measurable good, and ipilimumab only helps a small fraction of patients--around 10 percent. Still, in the clinical trial that led to approval of ipilimumab, more than half of the melanoma patients who responded to the drug survived for more than two years after taking it, and 20.8 percent survived for at least three years, compared to 12.2 percent of those who received the usual chemotherapy alone.

In 2009, researchers testing a new immunotherapy in kids with neuroblastoma stopped the trial early when it became clear that only 34 percent of children who received it saw their cancers return within two years, compared to 54 percent of those who didn't. The treatment targets a molecule called GD2 that is expressed by cancer cells, alerting the immune system to their whereabouts. In June, researchers announced that an experimental immunotherapy that targets a second brake in the immune system dramatically shrank tumors in 18 percent of lung cancer patients, 28 percent of melanoma patients, and 27 percent of kidney cancer patients.

If immunotherapy is proven to work against lung cancer, which kills more people than any other cancer, that will mark a major breakthrough for the strategy, says Jedd Wolchok, a researcher and physician at Memorial Sloan-Kettering who treated Esposito. He and other researchers are now testing these drugs in combination with targeted treatments, chemotherapy, radiation, and other immunotherapies. Experiences such as Esposito's suggest that immunotherapy becomes even more powerful when used together with these other approaches, says Wolchok.

Esposito's experience also shows the potential benefits of signing on for a clinical trial. Fewer than 10 percent of cancer patients enroll in trials, says Neal Meropol, chief of the division of hematology and oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University School of Medicine in Cleveland. He says many mistakenly believe that they may receive a placebo, or dummy pill, instead of treatment. In today's cancer treatment trials, Meropol says, patients in the experimental group typically receive the current standard treatment in addition to what's being tested; those assigned to the control group get standard care.

"We're getting smarter about how clinical trials are designed, and how patients are selected," he says. "The likelihood of deriving a personal benefit from a clinical trial may actually be increasing." Patients can find information about such trials through many sources, including search engines maintained by the National Cancer Institute and by individual cancer centers, and through patient advocacy groups.

Jeff Wigbels is a firm believer. The Atlanta marathon runner, 63, was diagnosed with lung cancer a few years ago, the night before his second child was born. A local doctor told Wigbels that he should start radiation and chemotherapy immediately, but first Wigbels sought a second opinion at MD Anderson. There, doctors helped him enroll in clinical trials and eventually tested Wigbel's tumor for ALK mutations. He tested positive, and started treatment taking aim at these mutations. A week later, Wigbels says, "I went from not being able to swallow food to having no cancer that they could see in my body."

Rounds of the targeted therapy, along with doses of radiation to his brain, where he has also developed small tumors, have mostly kept Wigbels's cancer in check since. This summer, he also enrolled in a trial of a second experimental drug targeted to ALK mutations that is designed to cross the blood-brain barrier. Having started a foundation called Take Aim at Cancer to fund research into targeted therapies, he describes his philosophy this way: "The Wigbels belief is that you've got to be as close as you can to research."

Attacking the seeds. Given cancer's deadly urge to spread, one of the most exciting research paths of the future takes on stem cells within tumors, which are thought to be very rare but uniquely able to renew themselves, drive tumor formation, and perhaps sneakily travel to distant locations. Evidence of stem cells has now been found in a number of cancers, including those of the blood, brain, breast, colon, and prostate. If doctors could wipe out or hobble these cells, they might be able to eliminate recurrences and improve response to treatment, because the cells are also thought to be responsible for tumors' resistance to chemotherapy.

In May, a team based at McMaster University in Ontario showed that an antipsychotic drug called thioridazine specifically killed leukemic cancer stem cells in the lab, while sparing healthy cells. And in June, a researcher from the Spanish National Cancer Research Centre in Madrid showed that the diabetes drug metformin killed pancreatic cancer stem cells, and--when combined with chemotherapy--killed mature cancer cells as well. Neither of these therapies has been shown to work on cancer stem cells in animals or humans. But the results are raising researchers' interest in moving them onto the ever-growing list of promising trials.

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